Vol 109, No 12 (2023)

Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their contractile effect in pulmonary arteries remains as high as in the pre-term fetus arteries and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulation and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods.

The development of coronavirus infection prevents the transport of oxygen to the tissues through the mechanism of impaired hemoglobin saturation in the damaged lung. The change in the affinity of hemoglobin for oxygen, which is the most important factor in compensating for oxygen deficiency in various pathological conditions, underlies the processes of adaptation to hypoxia. The question of the significance of the shift in the oxyhemoglobin dissociation curve in this pathology is actively discussed, in which its shift to the left in the arterial blood and its shift to the right in the venous blood are noted, which in the conditions of the development of the hypoxic syndrome reflects the a-ctivation of the body’s mechanisms to compensate for oxygen deficiency. The change in its position is not specific for this pathology, but is determined by the severity of oxygen deficiency and the imbalance of the mechanisms of the cardiorespiratory system, as well as the peculiarities of the status of patients and the analyzed blood sample.

In diabetes mellitus (DM) patients, the accumulation of advanced glycation end products (AGE) leads to inflammation and oxidative stress through the activation of specific receptors for AGE (RAGE). Glycated albumin (gHSA) makes a significant contribution to the overall level of AGE in human body and, as a result, to the pathogenesis of DM and concomitant diseases. The mechanism of interaction of gHSA with RAGE is practically not studied. The purpose of the present paper is to study the binding of gHSA to RAGE using molecular modeling methods, to find the main sites of interaction and structural features of glycation sites that determine the efficiency of complex formation with RAGE. Ten gHSA models were constructed using molecular docking and molecular dynamics (MD) methods; each model corresponded to one modified lysine residue (carboxymethyl-lysine): Lys64, Lys73, Lys137, Lys233, Lys262, Lys317, Lys378, Lys525, Lys573, Lys574. Complexes of gHSA with the V-domain of RAGE were constructed using the macromolecular docking method, and their stability was studied using MD simulation. In the constructed gHSA models, the carboxyl groups of glycated Lys317 and Lys525 form intramolecular salt bridges with surrounding amino acids; in other cases, the carboxyl groups of the modified lysines are free to interact with positively charged amino acid residues on the RAGE surface. According to the macromolecular docking data and subsequent MD simulation, the complex of RAGE with gHSA glycated at Lys233 is most effective in terms of strength and specificity. Specific RAGE complexes with gHSA glycated at Lys317 and Lys574 are not formed. The obtained data on the interaction of gHSA with RAGE will help to understand the role of albumin in the pathophysiology of DM and advance towards the prevention and development of effective therapy for this disease.

Histamine receptors play pivotal roles in various physiological functions, ranging from allergic responses to memory and sleep regulation, making them important drug targets. While second-generation antihistamines have been successfully used in rodents and humans, investigating their effects in non-traditional animal models enhances our understanding and aids the development of novel drug candidates. In this study, we examined the impact of the first-generation drug chloropyramine and the second-generation drugs loratadine and cetirizine, at concentrations of 1, 5, and 10 mg/L, on adult zebrafish b-ehavior using the novel tank test. All three drugs significantly altered fish locomotor a-ctivity, decreasing distance traveled and average velocity while increasing low acceleration frequency. Chloropyramine at 5 and 10 mg/L and loratadine at 1, 5, and 10 mg/L significantly reduced top entries compared to the control. Additionally, 5 mg/L chloropyramine increased the total duration of top entries, whereas loratadine at 10 mg/L r-educed this behavior compared to controls. Overall, chloropyramine and loratadine e-xhibited a sedative effect typical of antihistamines, while cetirizine solely reduced locomotor activity without affecting other patterns of fish behavior. Thus, cetirizine demonstrated the least impact on the central nervous system among the studied drugs, making it the optimal and safest choice among antihistamines.

The use of high-calorie nutrition can lead to morpho-functional changes of the vascular bed that have clinical importance, however, the modulatory effect of perivascular adipose tissue (PVAT) on the vascular system in this process remains poorly characterized. The aim of this work was to study the direct effect of PVAT on the contractile activity of rat aortic smooth muscle in metabolic disorders that occur when using the cafe diet (CD). It was shown that 7 weeks of keeping animals on this diet led to excessive accumulation of visceral adipose tissue, disorders of carbohydrate and lipid metabolism, manifested in the form of hyperglycemia and hypertriglyceridemia, which characterizes the development of the metabolic syndrome. An important functional role of PVAT in the regulation of vascular tone was demonstrated using wire myography on annular without endothelium segments of the thoracic aorta of the rat. In the control group of animals on a standard diet, the presence of PVAT reduced vasoconstriction caused by stimulation by phenylephrine. In the experimental group, in rats with the metabolic syndrome caused by DC, there was a decrease in the protective effect of PVAT. The implementation of this effect was carried out with the participation of voltage-dependent and/or Ca²⁺-activated K⁺-channels of smooth muscles, while the involvement of ATP-sensitive K⁺-channels was weak and independent from metabolic changes caused by the use of CD. Part of the anticontractile effect of PVAT was mediated through nitric oxide (NO) produced by PVAT itself. Under metabolic changes caused by CD, the endothelium-independent anticontractile effect of NO is completely eliminated without changing the sensitivity of vascular smooth muscles to it.

Depressive disorder is the most common psychopathology that can coexist with other mental illnesses such as post-traumatic stress disorder. It has been shown that there are gender differences in susceptibility to these psychopathologies. Mice of the mutant strain Disc1-Q31L are characterized by depressive-like behavior and disruption of the molecular pathways involved in the processes associated with fear memory. Gender and interstrain differences in the processes of learning and extinction of the conditioned response of passive avoidance were studied in male and female Disc1-Q31L mice and control C57BL/6 mice. It was shown that male and female mice of both strains learned equally well the conditioned response of passive avoidance, but differed in fear memory extinction, the ability to form a new safety memory trace in the previously dangerous dark compartment of the setup. However, there was a deficit in the extinction of the conditioned response of passive avoidance in C57BL/6 females compared to males, as well as interstrain differences in the dynamics of extinction in both females and males. Disc1-Q31L males reached full extinction later than C57BL/6 males, while Disc1-Q31L females did not exhibit extinction during the 24 days of the test. Thus, this work shows the interaction of the effect of gender and the Disc1-Q31L mutation on the processes of fear memory extinction.

The effect of forced running for 1 hour daily for 4 weeks on the content of Na⁺/K⁺-ATPase isoforms and monovalent cations in the skeletal muscles of mice with a model of type II diabetes mellitus (DM-II) was studied. To form a model of the disease, a high-fat diet was used, and physical activity in the form of forced running was carried out for 4 weeks. The content of Na⁺/K⁺-ATPase isoforms and Na⁺ and K⁺ ions in muscle tissue of m. gastrocnemius was determined by Western blotting and atomic absorption spectrophotomery, respectively. It has been shown that the formation of DM-II in mice is accompanied by changes in the content of Na⁺/K⁺-ATPase alpha 1 and 2 isoforms in muscle tissue. The effect of forced running loads on the content of Na⁺/K⁺-ATPase in muscle tissue is significant and primarily differs in age groups. One can also note a certain dependence of the influence of forced running loads on the content of this enzyme on the time of their use. In young animals, changes in the concentrations of monovalent sodium and potassium cations after forced running loads were less pronounced. In aged mice, against the background of forced loads, an increase in the content of sodium and decrease in the content of potassium in muscle tissue was observed. The detected changes in monovalent cations content in the muscle tissue of mice with diabetes mellitus II under the influence of forced running loads may play a role in the implementation of the metabolic effects of physical activity.

Chronically critically ill patients lose a significant amount of muscle mass during their stay in the intensive care unit, which can have long-term detrimental consequences. This, among other factors, leads to the degradation of the muscle cytoskeleton’s integrity, and at present there are no comprehensive studies that describe the mechanisms b-ehind the development of this process. The purpose of this study was to investigate the signaling processes that contribute to the degradation of desmin in patients with critical illness myopathy (CIM). Incisional muscle biopsies were taken from the soleus muscle from 6 patients undergoing treatment at the A.L. Polenov Russian Research Institute - branch of the Almazov National Medical Research Center, with chronic impairment of consciousness (lasting at least 2 months). Muscle biopsies taken from healthy men using a needle biopsy technique were used as controls. Biopsies were frozen in liquid nitrogen for subsequent Western blot and PCR analysis, as well as immunohistochemical studies. The analysis showed that fibers with an altered histological pattern of desmin were visually identified in 4 out of 6 patients studied. We also observed a significant decrease in desmin content by 69% and a 24% decrease in its mRNA content in patients with CIM. Desmin breakdown may be associated with increased calpain activity and activation of the ubiquitin-proteasome system. In this study, the content of calpain-1 increased under conditions of CIM at the protein level, but remained unchanged at the mRNA level. We observed changes in GSK3-β (Ser9) phosphorylation, which is a crucial step in the d-epolymerization of desmin filaments by calpain-1. A study on ubiquitin ligases revealed a significant 155% increase in the expression of Trim32, along with a decrease in the e-xpression of Atrogin1 and MuRF1. Thus, in this study, we observed a decrease in desmin content under conditions of CIM. The breakdown of desmin may be due to increased phosphorylation by GSK3β and subsequent cleavage by calpain-1. In addition, we observed an increase in the expression of the E3 ubiquitin ligase Trim32, the activity of which, according to literature, also increases after phosphorylation of desmin.